9/11 Neuroimmunophysiology of excessive alcohol intake

PROJECT SUMMARY/ABSTRACT This Integrative Neuroscience Initiative on Alcoholism (INIA-Neuroimmune, INIA-N) consortium component is for a U01 research project that seeks to determine how neuroimmune signaling molecules and glia contribute to neuronal adaptations in the nucleus accumbens that promote excessive ethanol drinking. Prior work by this INIA- N component identified neuronal adaptations in the nucleus accumbens (NAc) that are associated with excessive alcohol consumption. In particular, we found that ethanol dependence and excessive intake are associated with plasticity in glutamatergic synapses on dopamine D1 receptor-expressing medium spiny neurons (D1MSNs), which comprise a major output pathway of the NAc that is heavily involved in reward-based behaviors. Recently we discovered that, although synaptic excitation is enhanced, the membrane excitability of these neurons not only is suppressed during acute withdrawal from ethanol, but is strongly, inversely, correlated with prior ethanol intake. We will employ mouse behavioral models of chronic and excessive drinking, genetically engineered mice, and brain slice electrophysiology to test the hypothesis that neuroimmune activity contributes to these synaptic and membrane adaptations of D1MSNs. Specific aim 1 will evaluate how neuronal physiology is altered by the cytokine interleukin-33 (IL-33) in an ethanol-dependent manner, and it will use genetically-engineered mice for inducible and conditional deletion of IL-33, or its receptor, from specific cell types (microglia, astrocytes, and/or neurons) to probe the role of this signaling pathway in the escalation of alcohol intake. Specific aim 2 will take a broader approach, using brain slice electrophysiology to ask whether NAc microglia exhibit functional adaptations that correlate with alcohol intake and its associated adaptations in D1MSNs. Specific aim 3 will be collaborative studies on other neuroimmune signaling and regulatory molecules identified by INIA-N investigators’ as playing a role in excessive alcohol intake. Here we will again use brain slice electrophysiology and will determine whether manipulations of these neuroimmune molecules may alter NAc D1MSN physiology to regulate alcohol consumption. These studies will serve the mission of NIAAA by generating new, fundamental knowledge about the effects of alcohol on brain health, and seeks to apply such knowledge to identify new targets for the treatment of excessive alcohol consumption.